Calcitonin gene-related peptide-expressing sensory neurons and spinal microglial reactivity contribute to pain states in collagen-induced arthritis

Objective To evaluate the contribution of sensory neurons in ankle joints and adjacent tissue to the development of pain in collagen‐induced arthritis (CIA), and to determine the relationship between pain and the appearance of clinical signs. Methods Mechanical and heat hypersensitivity and hind paw swelling were assessed in Lewis rats before and until 18 days following collagen immunization. We examined the effect of intrathecal administration of a calcitonin gene‐related peptide (CGRP) antagonist (CGRP8–37) from day 11 to day 18 postimmunization on CIA‐induced hypersensitivity. During CIA development, CGRP and p‐ERK immunoreactivity was quantified in lumbar dorsal root ganglia in which sensory neurons innervating the ankle joint were identified by retrograde labeling with Fluoro‐Gold. Microgliosis in the lumbar dorsal horn was assessed by immunohistochemistry, and release of CGRP evoked by activity of primary afferent fibers was measured using a preparation of isolated dorsal horn with dorsal roots attached. Results CIA was associated with mechanical hypersensitivity that was evident before hind paw swelling and that was exacerbated with the development of swelling. Heat hyperalgesia developed along with swelling. Concomitant with the development of mechanical hypersensitivity, joint innervating neurons exhibited enhanced CGRP expression and an activated phenotype (increased p‐ERK expression), and significant microgliosis became evident in the dorsal horn; these peripheral and central changes were augmented further with disease progression. CGRP release evoked by dorsal root stimulation was higher in the dorsal horn on day 18 in rats with CIA compared to control rats. Prolonged intrathecal administration of CGRP8–37 attenuated established mechanical hypersensitivity and reduced spinal microgliosis. Conclusion Sensory neuron–derived CGRP sustains mechanical hypersensitivity and spinal microglial reactivity in CIA, suggesting that central mechanisms play critical roles in chronic inflammatory pain. Blockade of these central events may provide pain relief in rheumatoid arthritis patients

The Fundamental Line of the Local Group Satellites

We present a new correlation between the mass-to-light (M/L) ratio and the mean metallicity for the satellites of the Local Group. This relation together with their central surface brightness define a Fundamental Line where metal poor and low surface brightness dwarfs are dark matter dominated while metal rich high surface brightness systems will have a low M/L ratio. This Fundamental Line is independent of distance to the central galaxy (M31 and the Milky Way) and morphological type among other global parameters as their star formation history. The new M/L-metallicity relation indicates that dwarf spheroidal galaxies are dark matter confined. It can be interpreted if satellites experienced a continuous loss of metals with a final episode of gas ejection at the end of the star formation epoch. Only Globular Clusters are found to lie outside the Fundamental Line of dwarf satellites. Unlike satellite galaxies they are not dark matter confined.Comment: 9 pages,2 figures. Submitted to ApJ Letter

Spike burst-pause dynamics of Purkinje cells regulate sensorimotor adaptation

Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of target medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.This work was supported by the European Union (www.europa.eu), Project SpikeControl 658479 (recipient NL), the Spanish Agencia Estatal de Investigacio´n and European Regional Development Fund (www.ciencia.gob.es/ portal/site/MICINN/aei), Project CEREBROT TIN2016-81041-R (recipient ER), and the French National Research Agency (www.agence-nationalerecherche. fr) – Essilor International (www.essilor. com), Chair SilverSight ANR-14-CHIN-0001 (recipient AA)

Neuron-immune mechanisms contribute to pain in early stages of arthritis

Background: Rheumatoid arthritis (RA) patients frequently show weak correlations between the magnitude of pain and inflammation suggesting that mechanisms other than overt peripheral inflammation contribute to pain in RA. We assessed changes in microglial reactivity and spinal excitability and their contribution to pain-like behaviour in the early stages of collagen-induced arthritis (CIA) model. Methods: Mechanically evoked hypersensitivity, spinal nociceptive withdrawal reflexes (NWRs) and hind paw swelling were evaluated in female Lewis rats before and until 13 days following collagen immunization. In the spinal dorsal horn, microgliosis was assayed using immunohistochemistry (Iba-1/p-p38) and cyto(chemo)kine levels in the cerebrospinal fluid (CSF). Intrathecal administration of microglia-targeting drugs A-438079 (P2X7 antagonist) and LHVS (cathepsin S inhibitor) were examined upon hypersensitivity, NWRs, microgliosis andcyto(chemo)kine levels in the early phase of CIA. Results: The early phase of CIA was associated with mechanical allodynia and exaggerated mechanically evoked spinal NWRs, evident before hind paw swelling, and exacerbated with the development of swelling. Concomitant with the development of hypersensitivity was the presence of reactive spinal microgliosis and an increase of IL-1β levels in CSF (just detectable in plasma). Prolonged intrathecal administration of microglial inhibitors attenuated the development of mechanical allodynia, reduced microgliosis and attenuated IL-1β increments. Acute spinal application of either microglial inhibitor significantly diminished the sensitization of the spinal NWRs. Conclusions: Mechanical hypersensitivity in the early phase of CIA is associated with central sensitization that is dependent upon microglial-mediated release of IL-1β in the spinal cord. Blockade of these spinal events may provide pain relief in RA patients

Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice

Background Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations. The sigma-1 receptor (σ1R) is a ligand-regulated molecular chaperone involved in mitochondrial calcium homeostasis and pain hypersensitivity. This receptor plays a key role in paclitaxel-induced neuropathic pain, but it is not known whether it also modulates mitochondrial abnormalities. In this study, we used a mouse model of paclitaxel-induced neuropathic pain to test the involvement of the σ1R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (σ1R knockout mice) and pharmacological (σ1R antagonist) approaches.Results Paclitaxel administration to wild-type (WT) mice produced cold- and mechanical-allodynia, and an increase in the frequency of swollen and vacuolated mitochondria in myelinated A-fibers, but not in C-fibers, of the saphenous nerve. Behavioral and mitochondrial alterations were marked at 10 days after paclitaxel-administration and had resolved at day 28. In contrast, paclitaxel treatment did not induce allodynia or mitochondrial abnormalities in σ1R knockout mice. Moreover, the prophylactic treatment of WT mice with BD-1063 also prevented the neuropathic pain and mitochondrial abnormalities induced by paclitaxel.Conclusions These results suggest that activation of the σ1R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, σ1R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy.This study was partially supported by grant P11-CTS-7649 and grant CTS-109 from Junta de Andalucía, FEDER funds, a grant from Esteve, and a grant from the Centro para el Desarrollo Tecnológico Industrial (NeoGenius Pharma project). F. R. Nieto was supported by a FPU grant from the Spanish Ministerio de Educación y Ciencia (MEC) and C. M. Cendán by the Research Program of the University of Granada

Semiclassical energy formulas for power-law and log potentials in quantum mechanics

We study a single particle which obeys non-relativistic quantum mechanics in R^N and has Hamiltonian H = -Delta + V(r), where V(r) = sgn(q)r^q. If N \geq 2, then q > -2, and if N = 1, then q > -1. The discrete eigenvalues E_{n\ell} may be represented exactly by the semiclassical expression E_{n\ell}(q) = min_{r>0}\{P_{n\ell}(q)^2/r^2+ V(r)}. The case q = 0 corresponds to V(r) = ln(r). By writing one power as a smooth transformation of another, and using envelope theory, it has earlier been proved that the P_{n\ell}(q) functions are monotone increasing. Recent refinements to the comparison theorem of QM in which comparison potentials can cross over, allow us to prove for n = 1 that Q(q)=Z(q)P(q) is monotone increasing, even though the factor Z(q)=(1+q/N)^{1/q} is monotone decreasing. Thus P(q) cannot increase too slowly. This result yields some sharper estimates for power-potential eigenvlaues at the bottom of each angular-momentum subspace.Comment: 20 pages, 5 figure

(1+1) Schrodinger Lie bialgebras and their Poisson-Lie groups

All Lie bialgebra structures for the (1+1)-dimensional centrally extended Schrodinger algebra are explicitly derived and proved to be of the coboundary type. Therefore, since all of them come from a classical r-matrix, the complete family of Schrodinger Poisson-Lie groups can be deduced by means of the Sklyanin bracket. All possible embeddings of the harmonic oscillator, extended Galilei and gl(2) Lie bialgebras within the Schrodinger classification are studied. As an application, new quantum (Hopf algebra) deformations of the Schrodinger algebra, including their corresponding quantum universal R-matrices, are constructed.Comment: 25 pages, LaTeX. Possible applications in relation with integrable systems are pointed; new references adde